Selenium (Se) is an essential trace element that plays a critical role in many biological processes, such as reproduction, thyroid hormone metabolism, DNA synthesis, and protection from oxidative damage and infection. Selenium is incorporated at the catalytic site of various selenium dependent enzymes such as glutathione peroxidase (GPx), thioredoxin reductases, and one methionine-sulfoxidereductase. These selenoenzymes contribute to regulation of metabolic activity, immune function, antioxidant defense, intracellular redox regulation, and mitochondrial function.
Results in the literature indicate that different chemical forms of selenium have different bioactivities. For example, a selenozolidine was more effective at reducing the number of lung tumors than selenomethionine. (Poerschke et al, J Biochem Molecular Toxicology 2012 26:344). Barger et al. showed that mice fed different sources of selenium, for example, selenium methionine, sodium selenite and selenized yeast, had differential effects on gene expression and on specific functional pathways of mitochondrial structure and function. (Barger et al, Genes and Nutrition 2012 7:155). Selenized yeast contains many selenium and sulfur compounds but not all of the selenium compounds in selenized yeast impact biological processes. In addition, a mixture of selenium and sulfur compounds in selenized yeast have been shown to be inhibitory to each other, to negatively impact biological processes, or be toxic to cells.
Alzheimer's Disease is the sixth leading cause of death in the United States of America, and is the most common form of dementia. Currently, Alzheimer's Disease (“AD”) is estimated to affect 5.1 million people in America. There are two types of AD; Early-Onset AD, which occurs before the age of 65, and Late-Onset AD, which occurs after the age of 65. Late- and Early-Onset AD are histopathologically characterized by two types of brain lesions, senile plaques and Neurofibrillary Tangles or NFTs.
The Amyloid Beta protein (Abeta or Aβ) is the main component of senile plaques, which are often referred to as Aβ plaques. The Aβ protein is 36-43 amino acids of the larger Amyloid Precursor Protein (APP). Plaques are formed when APP is aberrantly processed by two enzymes, β-secretase and γ-secretase, resulting in the formation of the Aβ peptide. Neprilysin is an amyloid-degrading enzyme that may be regulated by APP.
NFTs are composed of hyper-phosphorylated forms of the microtubule-associated protein, Tau. In particular, the p38 gene pathway is known to be involved in Tau phosphorylation associated with AD.
Literature evidence supports the idea that both Aβ plaques and NFTs are crucial partners in the pathogenesis of Alzheimer's Disease, and that they act individually and in concert to maximize cognitive impairment and neuronal loss in affected individuals. For example, mutations in Amyloid Precursor Protein (APP) are known to induce AD with 100% penetration. Familial AD (FAD)-associated mutations of APP, presenilin-I (PSEN-I) and presenilin-2 (PSEN-2), also lead to an increased level of Aβ protein generation and aggregation.
In addition, the Apolipoprotein E (APOE) gene has been associated with AD. In particular, specific alleles of the APOE gene have been associated with Late-Onset AD. For example, the presence of an APOE4 allele indicates an increased risk of developing Late-Onset AD. However, the role that the APOE4 allele plays in the AD disease process is not known.
The apparent difference in bioactivity and availability of distinct chemical forms of selenium requires identification of compounds containing selenium that positively impact biological processes. In particular, there is a need to characterize the effects of selenium on β amyloid aggregation, Tau and p38 phosphorylation, and APOE4 and Neprilysin gene expression. Further, there is a need to determine the effect of selenium compounds and their efficacy on treating and/or preventing Alzheimer's Disease.